Pyridine structure-containing xanthoxylin ether derivative as well as preparation method and antibacterial application thereof

Abstract

The invention discloses a series of xanthoxylin ether derivatives containing pyridine structures as well as a preparation method and antibacterial application of the xanthoxylin ether derivatives. According to the series of compounds, a natural compound xanthoxylin is taken as a guide, structural optimization is carried out on a methoxy group of the natural compound xanthoxylin, and a sulfydryl pyridine quaternary ammonium salt fragment is introduced, so that a series of xanthoxylin ether derivatives containing pyridine structures are prepared, and the structural general formula of the xanthoxylin ether derivatives is shown as a formula (I). The series of compounds have high in-vivo and in-vitro antibacterial activity on Staphylococcus aureus ATCC 29213 and clinically separated methicillin-resistant Staphylococcus aureus (MRSA), and the antibacterial activity of the compounds is equivalent to that of a clinical first-line drug vancomycin. Through structural optimization, the water solubility and antibacterial activity of the xanthoxylin are enhanced, and the xanthoxylin has relatively low in-vivo and in-vitro toxicity and hemolytic activity and is not easy to generate drug resistance. Therefore, the xanthoxylin ether derivatives containing the pyridine structure have the potential of being further developed into novel antibacterial drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to pyridine-containing Zanthoxylum bungeanum toxin ether derivatives, a preparation method thereof, and antibacterial applications. Background Art

[0002] Antibiotic resistance has become a serious threat to global human health. The overuse of antibiotics has promoted bacterial resistance mutations, making almost all clinically used antibiotics show resistance in different strains. Methicillin-resistant Staphylococcus aureus (MRSA), as a super-resistant bacterium, can cause a variety of serious invasive infections such as pneumonia, necrotizing fasciitis, sepsis, infective endocarditis and osteomyelitis. It poses a great threat to clinical practice due to its strong virulence and strong drug resistance. Therefore, there is an urgent need to develop new antibacterial agents to combat MRSA infections. In terms of its structural modification and activity against drug-resistant bacteria, there are few studies on Zanthoxylum bungeanum toxins, and its parent body itself has relatively poor water solubility and relatively poor antibacterial activity, leaving much room for improvement.

[0003] In recent years, quaternary ammonium salts (QAS) have become a hot topic in the research and development of antibacterial drugs due to their broad-spectrum antibacterial effects. However, the low selectivity and high cytotoxicity of quaternary ammonium salts limit their clinical application. Natural products are an important treasure trove for discovering and exploring drugs. People have found that natural products and their semi-synthetic analogues have played a vital role in the description and expansion of antibacterial drugs. Xanthotoxin (XAT), a furanocoumarin (linear), is found in the highest content in the fruits of peppers of the Rutaceae family and the roots of Oxalis of the Umbelliferae family. It has anti-inflammatory, antioxidant, anticonvulsant, anxiety, and antibacterial properties. It is an important lead molecule in drug research, but its antibacterial activity and solubility need to be further improved. Summary of the Invention

[0004] Purpose of the invention: In response to the above technical problems, the present invention provides a pyridine-containing zanthoxylum toxin ether derivative, a preparation method thereof, and an antibacterial application. The pyridine-containing zanthoxylum toxin ether derivative, a preparation method thereof, and an antibacterial application thereof have excellent in vitro and in vivo antibacterial effects on Gram-positive bacteria such as Staphylococcus aureus (S. aureus) ATCC 29213 and various clinically isolated MRSA, and solve problems such as poor water solubility.

[0005] Technical solution: In order to achieve the above-mentioned purpose of the invention, the technical solution adopted by the present invention is as follows:

[0006] The ether derivative of Zanthoxylum bungeanum containing a pyridine structure or a pharmaceutically acceptable salt thereof has a structure as shown in the following formula (I):

[0007]

[0008] wherein n=3, 4 or 5, and R1 and R2 are independently selected from H or C2-C8 alkyl.

[0009] As a specific embodiment, in the formula (I), Located at the ortho or para position of the N atom on the pyridine group, said R1 and R2 are independently selected from H or C4-C6 alkyl.

[0010] As a specific embodiment, in the formula (I), When located in the para position relative to the nitrogen atom of the pyridine group, n, R1 and R2 are (1) to (15) in the following combinations, When located in the ortho position of the nitrogen atom on the pyridine group, n, R1 and R2 are (16)-(30) in the following combinations:

[0011] (1)n=3, R1=H, R2=-CH2CH2CH2CH3; (2)n=3, R1=H, R2=-CH2CH2CH2CH2CH3;

[0012] (3)n=3, R1=H, R2=-CH2CH2CH2CH2CH2CH3; (4)n=3, R1=R2=-CH2CH2CH2CH3;

[0013] (5)n=3, R1=R2=-CH2CH(CH3)2; (6)n=4, R1=H, R2=-CH2CH2CH2CH3;

[0014] (7)n=4, R1=H, R2=-CH2CH2CH2CH2CH3;

[0015] (8)n=4, R1=H, R2=-CH2CH2CH2CH2CH2CH3;

[0016] (9)n=4,R1=R2=-CH2CH2CH2CH3 (10)n=4,R 1 =R 2 =-CH2CH(CH3)2;

[0017] (11)n=5, R1=H, R2=-CH2CH2CH2CH3; (12)n=5, R1=H, R2=-CH2CH2CH2CH2CH3;

[0018] (13)n=5, R2=-CH2CH2CH2CH2CH2CH3; (14)n=5, R1=R2=-CH2CH2CH2CH3;

[0019] (15)n=5, R1=R2=-CH2CH(CH3)2; (16)n=3, R1=H, R2=-CH2CH2CH2CH3;

[0020] (17)n=3, R1=H, R2=-CH2CH2CH2CH2CH3;

[0021] (18)n=3, R1=H, R2=-CH2CH2CH2CH2CH2CH3; (19)n=3, R1=R2=-CH2CH2CH2CH3;

[0022] (20)n=3, R1=R2=-CH2CH(CH3)2; (21)n=4, R1=H, R2=-CH2CH2CH2CH3;

[0023] (22)n=4, R1=H, R2=-CH2CH2CH2CH2CH3;

[0024] (23)n=4, R1=H, R2=-CH2CH2CH2CH2CH2CH3;

[0025] (24)n=4,R1=R2=-CH2CH2CH2CH3; (25)n=4,R 1 =R 2 =-CH2CH(CH3)2;

[0026] (26)n=5, R1=H, R2=-CH2CH2CH2CH3; (27)n=5, R1=H, R2=-CH2CH2CH2CH2CH3;

[0027] (28)n=5, R2=-CH2CH2CH2CH2CH2CH3; (29)n=5, R1=R2=-CH2CH2CH2CH3;

[0028] (30)n=5, R1=R2=-CH2CH(CH3)2.

[0029] The above specific selections represent compounds 1-30 in the following examples (each compound corresponds to a combination selection with the same serial number as above).

[0030] As a specific embodiment, the pharmaceutically acceptable salt of the pyridine-containing zanthoxylum toxin ether derivative is selected from bromide salt, chloride salt or iodide salt; preferably, the pharmaceutically acceptable salt of the pyridine-containing zanthoxylum toxin ether derivative is a bromide salt, and its structure is shown below:

[0031]

[0032] The present invention also provides a method for preparing the pyridine-containing Zanthoxylum bungeanum ether derivatives, comprising the following steps:

[0033] (1) Using Zanthoxylum bungeanum toxin as a substrate, the methoxy group is converted into a phenolic hydroxyl group under the action of a demethylation reagent to obtain intermediate a;

[0034] (2) Intermediate a reacts with different dibromoalkanes under alkaline conditions to synthesize intermediate b;

[0035] (3) Intermediate b reacts with mercaptopyridine under alkaline conditions to generate intermediate c;

[0036] (4) Intermediate c then reacts with intermediate d to generate the pyridine-containing zanthoxylum bungeanum ether derivative, as shown in the following reaction formula:

[0037]

[0038] Wherein, R1, R2 and n are the same as described above, and R3 is selected from Br, Cl or I.

[0039] As a specific embodiment, in step (1), the demethylation agent is selected from boron tribromide, the reaction molar ratio of the zanthoxylum toxin to boron tribromide is 1:3-1:6, the reaction temperature is 0°C, and the reaction solvent is anhydrous dichloromethane.

[0040] As a specific embodiment, in step (2), the base in the alkaline condition is K2CO3, the reaction molar ratio of intermediate a to the base is 1:1-1:1.5, the molar ratio of intermediate a to dibromoalkane is 1:1.5-1:3, the reaction temperature is 70-90°C, and the reaction solvent is anhydrous acetonitrile.

[0041] As a specific embodiment, in step (3), the base in the alkaline condition is K2CO3, the reaction molar ratio of intermediate b to the base is 1:1-1:1.5, the molar ratio of intermediate a to 4-mercaptopyridine / 2-mercaptopyridine is 1:1-1:1.5, the reaction temperature is 80°C, and the reaction solvent is anhydrous acetonitrile.

[0042] As a specific embodiment, in step (4), the preparation method of the intermediate d comprises the following steps: different amines reacting with compound II under the catalysis of triethylamine to produce intermediate d, wherein the molar ratio of amine to compound II and triethylamine is 1:1.5:1.5, the reaction temperature is 0°C, and the reaction solvent is anhydrous dichloromethane;

[0043]

[0044] Wherein, R1 and R2 are as described above, and R3 is selected from Br, Cl or I;

[0045] As a specific embodiment, in step (4), the molar ratio of intermediate c to intermediate d is 1:2-1:4, the reaction temperature is 70-90°C, and the reaction solvent is anhydrous acetonitrile.

[0046] Finally, the present invention provides the use of the pyridine-containing Zanthoxylum bungeanum ether derivative or its pharmaceutically acceptable salt in the preparation of antibacterial drugs. Preferably, the use is in the preparation of drugs for inhibiting Staphylococcus aureus (ATCC 29213) and various clinical methicillin-resistant Staphylococcus aureus (MRSA).

[0047] The compounds of the present invention are designed and synthesized by drawing on the structure and function of antimicrobial peptides to design and synthesize a series of Zanthoxylum bungeanum ether derivatives containing pyridinium quaternary ammonium salts. The parent structure in the derivatives as a hydrophobic part is conducive to the compound's insertion into the bacterial phospholipid bilayer membrane, and the hydrophilic cationic part is conducive to interaction with the negatively charged bacterial cell membrane, thereby causing bacterial death. The present invention evaluated the antibacterial activity of all target compounds and found that all target compounds showed good in vitro antibacterial activity against Staphylococcus aureus ATCC29213 and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC≤128μg / mL). In particular, the in vitro and in vivo anti-MRSA activity of the preferred compound 13 is comparable to that of the positive control drug vancomycin. In addition, the target compound has low hemolytic activity, in vivo toxicity, good water solubility and stability. Therefore, such compounds have broad prospects for clinical application.

[0048] Technical effect: The ether derivatives of zanthoxylum bungeanum containing pyridinium quaternary ammonium salt prepared by the present invention have good in vivo and in vitro antibacterial effects on Gram-positive bacteria such as Staphylococcus aureus ATCC 29213 and various methicillin-resistant Staphylococcus aureus (MRSA), while also improving water solubility, reducing biological toxicity, and having a high yield, and are expected to be further developed into potential clinical antibacterial drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The dynamic bactericidal curve of compound 13

[0050] Figure 2 This is a study on the drug resistance induction of compound 13.

[0051] Figure 3 The blood routine and blood biochemical indexes of compound 13 in vivo.

[0052] Figure 4 The changes in bacterial load on mouse skin in response to compound 13.

[0053] Figure 5 Compound 131 H-NMR spectrum.

[0054] Figure 6 Compound 13 13 C-NMR spectrum. DETAILED DESCRIPTION

[0055] The present invention is further described in detail below through examples.

[0056] Example 1 Preparation of Intermediate a

[0057] Zanthoxylum bungeanum toxin (1 mmol) was dissolved in 5 mL of anhydrous dichloromethane in a 25 mL round-bottom flask, protected by a nitrogen balloon, and stirred in an ice bath. After 5 minutes, boron tribromide (6 mmol) was slowly added dropwise. The mixture was stirred for approximately 2 hours, and the reaction progress was monitored by TLC. After the reaction, the reaction solution was slowly poured into ice water. A large amount of solid precipitated, which was filtered using a Buchner funnel, washed with water, and dried in a 50°C oven to obtain a yellow solid a with a yield of 93.0%.

[0058] Example 2 Preparation of Intermediate b1-3

[0059] Compound 2 (1 mmol) was weighed into a 50 mL round-bottom flask. 1,3-Dibromopropane / 1,4-Dibromobutane / 1,5-Dibromopentane (3 mmol) was added and dissolved in 5 mL of acetonitrile. The mixture was heated under reflux for approximately 12 h, and the reaction progress was monitored by TLC. After completion of the reaction, the mixture was extracted with dichloromethane. The combined dichloromethane layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (silica gel) was performed using a developing solvent of petroleum ether:ethyl acetate = 3:1 to obtain b1-3 as a white solid with yields of 88.3%, 87.4%, and 83.9%, respectively.

[0060] Example 3 Preparation of Intermediate c1-6

[0061] Weigh compound b1-3 (1 mmol) separately in a 25 mL round-bottom flask, add 4-mercaptopyridine / 2-mercaptopyridine (1.5 mmol) and potassium carbonate (1.5 mmol) respectively, use 5 mL acetonitrile as solvent, nitrogen balloon protection, heat reflux and stir for about 12-16 h, and monitor the reaction progress by TLC. After the reaction is completed, vacuum dryness is achieved, and extraction is performed with ethyl acetate and water. The ethyl acetate layer is combined after three extractions, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (silica gel column) is performed using a developing solvent of dichloromethane: ethyl acetate: methanol = 5:5:1 to obtain c1-6 as a yellow solid with a yield of 64.2%-73.0%.

[0062] Example 4 Preparation of Intermediate d

[0063] Weigh different secondary / tertiary amines (1 mmol) into a 25 mL round-bottom flask, then add triethylamine (1.5 mmol), dissolve in 5 mL of anhydrous dichloromethane, protect with a nitrogen balloon, and stir in an ice bath. After 5 minutes, slowly add bromoacetyl bromide (1.5 mmol) dropwise, gradually increase the reaction temperature from 0°C to room temperature, stir for about 6-12 hours, and monitor the reaction by TLC. After the reaction is completed, slowly pour the reaction solution into ice water to quench the bromoacetyl bromide until no white smoke appears. Extract with dichloromethane, extract three times, combine the dichloromethane layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oil a.

[0064] Example 5 Compound 1

[0065] Compound c1-6 (1 mmol) was weighed separately into a threaded pressurized vial, and compound d (3 mmol) was added. Using 3 mL of acetonitrile as the solvent, the vial was sealed and heated under reflux for approximately 10 hours, with reaction progress monitored by TLC. After completion of the reaction, column chromatography was performed using a developing solvent of dichloromethane:methanol = 10:1 to obtain the pure target compound (the bromide salt of compound 1, which contains a quaternary pyridinium ammonium salt structure, was obtained; the same procedure was used for the following compounds).

[0066] The physicochemical properties of compound 1 are as follows:

[0067] 1) White solid;

[0068] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0069] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.65(d,J=6.8Hz,2H,-Ph),8.51(t,J=5.6Hz,1H,NH),8.18(d,J=10.0Hz,1H,-CH=CH-),8.13(d,J=2.0Hz,1H ,-CH=CH-),8.04(d,J=6.8Hz,2H,-Ph),7.73(s,1H,-Ph),7.13(d,J=2.0Hz,1H,-CH=CH-),6.46(d,J=9.6Hz,1H,-CH= CH-),5.25(s,2H,-CH2-),4.56(t,J=6.0Hz,2H,-CH2-),3.58(t,J=7.2Hz,2H,-CH2-),3.14(dd,J=6.4,12.8Hz,2H,- CH2-),2.22(t,J=6.8Hz,2H,-CH2-),1.40-1.48(m,2H,-CH2-),1.28-1.35(m,2H,-CH2-),0.89(t,=7.2Hz,3H,-CH3); 13 CNMR(100MHz DMSO)δ:164.4,162.4,159.6,148.0,147.2,145.4,144.3,143.6,142.8,130.6,125.8, 122.2,116.4,114.6,107.3,72.0,60.0,38.8,30.9,28.4,27.1,19.4,13.7; HRMS(ESI)C 25 H 27 N2O5S[M-Br] + calcd=467.1635; found=467.1645.

[0070] Example 6 Compound 2

[0071] Compound 2 was synthesized using the method described in Example 5. The physicochemical properties of compound 2 are as follows:

[0072] 1) Yellow solid;

[0073] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0074] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.67(d,J=6.0Hz,3H,-Ph,NH),8.19(d,J=9.6Hz,1H,-CH=CH-),8.13(s,1H,-CH=CH-),8.0 4(d,J=6.0Hz,2H,-Ph),7.73(s,1H,-Ph),7.12(s,1H,-CH=CH-),6.46(d,J=9.6Hz,1H,-CH=CH-),5. 27(s,2H,-CH2-),4.56(t,J=5.2Hz,2H,-CH2-),3.58(t,J=6.4Hz,2H,-CH2-),3.12(d,J=5.6Hz,2H ,-CH2-),2.22(t,J=6.0Hz,2H,-CH2-),1.45(s,2H,-CH2-),1.28(s,4H,-CH2-),0.87(s,3H,-CH3); 13 C NMR(100MHz DMSO)δ:166.5,162.7,159.9,148.0,147.2,145.3,144.2,142.9,130.7,125.9,122.6, 116.6,114.2,107.1,72.1,60.1,32.1,28.5,28.4,27.1,21.8,13.9,13.7; HRMS(ESI)C 26 H 29 N2O5S[M-Br] + calcd=481.1792; found=481.1795.

[0075] Example 7 Compound 3

[0076] Compound 3 was synthesized using the method described in Example 5. The physicochemical properties of compound 3 are as follows:

[0077] 1) Yellow solid;

[0078] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0079] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.65(d,J=6.8Hz,2H,-Ph),8.58(t,J=5.2Hz,1H,NH),8.18(d,J=9.6,1H,-CH=CH-),8.13(d,J=2.0Hz,1H,- CH=CH-),8.04(d,J=6.8Hz,2H,-Ph),7.74(s,1H,-Ph),7.13(d,J=2.0Hz,1H,-CH=CH-),6.46(d,J=9.2Hz,1H,-CH=C H-),5.26(s,2H,-CH2-),4.56(t,J=5.6Hz,2H,-CH2-),3.58(t,J=7.2Hz,2H,-CH2-),3.08-3.11(m,2H,-CH2-),2.1 8-2.27(m,2H,-CH2-),1.40-1.49(m,2H,-CH2-),1.19-1.27(m,6H,-CH2-),0.87(t,J=6.4Hz,3H,-CH3); HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=495.1948; found=495.1956.

[0080] Example 8 Compound 4

[0081] Compound 4 was synthesized using the method described in Example 5. The physicochemical properties of compound 4 are as follows:

[0082] 1) Light yellow liquid;

[0083] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0084] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz CDC13)δ:7.60(d,J=9.6Hz,1H,-CH=CH-),7.27(d,J=9.2Hz,1H,-Ph),6.80(d,J=8.8Hz,1H,-Ph),6.24(d,J=9.6 Hz,1H,-CH=CH-),5.15(t,J=6.8Hz,1H,-CH=C(CH3)2),5.00(s,2H,-CH2-),4.20(t,J=5.6Hz,2H,-CH2-),4.14- 4.18(m,2H,-CH2-),3.65(s,6H,N-CH3),3.50(d,J=7.2Hz,4H,-CH2-),3.36-3.39(m,2H,-CH2-),2.40-2.44(m, 2H,-CH2-),1.83(s,3H,-CH3),1.66(s,3H,CH3),1.25-1.29(m,3H,-CH3),1.11-1.15(m,3H,-CH3); HRMS(ESI)C 25 H 37 N2O4[M-Br] + calcd=429.2748; found=429.2764.

[0085] Example 9 Compound 5

[0086] Compound 5 was synthesized using the method described in Example 5. The physicochemical properties of compound 5 are as follows:

[0087] 1) Orange solid;

[0088] 2) The NMR spectrum of the compound ( 1 HNMR, 400 MHz) characteristics:

[0089] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO) δ: 8.64 (d, J = 7.2Hz, 2H, -Ph), 8.18 (d, J = 9.6Hz, 1H, -CH = CH-), 8.13 (d, J = 2.4Hz, 1H, -CH = CH-), 8.06 (d, J = 6. 8Hz,2H,-Ph),7.74(s,1H,-Ph),7.13(d,J=2.0Hz,1H,-CH=CH-),6.46(d,J=9.6Hz,1H,-CH=CH-),5.60(s,2H,-CH2 -),4.57(t,J=6.0Hz,2H,-CH2-),3.59(t,J=7.2Hz,2H,-CH2-),3.17(dd,J1=3.4Hz,J2=7.2Hz,4H,-CH2-),2.20-2 .27(m,2H,-CH-),1.94-2.06(m,2H,-CH2-),0.95(d,J=6.4Hz,6H,-CH2-),0.83(d,J=7.2Hz,6H,-CH3); HRMS(ESI)C 29 H 35 N2O5S[M-Br] + calcd=523.2261; found=523.2271.

[0090] Example 10 Compound 6

[0091] Compound 6 was synthesized using the method described in Example 5. The physicochemical properties of compound 6 are as follows:

[0092] 1) Yellow solid;

[0093] 2) The NMR spectrum of the compound ( 1 HNMR, 400 MHz) characteristics:

[0094] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.67(d,J=4.8Hz,1H,NH),8.63(d,J=6.8Hz,2H,-Ph,),8.17(t,J=9.6Hz,1H,-CH=CH-),8.12(d,J=2.0Hz,1H, -CH=CH-),7.99(d,J=6.8Hz,2H,-Ph),7.71(s,1H,-Ph),7.11(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH -),5.26(s,2H,-CH2-),4.48(d,J=4.8Hz,2H,-CH2-),3.41(d,J=6.4Hz,2H,-CH2-),3.13(dd,J=6.4,12.4Hz,2H,-CH2 -),1.96(s,4H,-CH2-),1.39-1.47(m,2H,-CH2-),1.29-1.34(m,2H,-CH2-),0.88(t,J=7.2Hz,3H,-CH3); HRMS(ESI)C 26 H 39 N2O5S[M-Br] + calcd=481.1792; found=481.1800.

[0095] Example 11 Compound 7

[0096] Compound 7 was synthesized using the method described in Example 5. The physicochemical properties of compound 7 are as follows:

[0097] 1) Yellow solid;

[0098] 2) The NMR spectrum of the compound ( 1 HNMR, 400 MHz) characteristics:

[0099] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.62(d,J=6.8Hz,3H,NH,-Ph,),8.17(d,J=9.6Hz,1H,-CH=CH-),8.12(d,J=2.4Hz,1H,-CH=CH-),7.99(d,J =6.8Hz,2H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.24(s,2H,-C H2-),4.47(t,J=5.6Hz,2H,-CH2-),3.42(t,J=6.8Hz,2H,-CH2-),3.12(dd,J=6.4,12.4Hz,2H,-CH2-),1.96(t,J=2 .4Hz,4H,-CH2-),1.45(t,J=7.2Hz,2H,-CH2-),1.26-1.31(m,2H,-CH2-),0.87(t,J=6.8Hz,3H,-CH3); HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=495.1948; found=495.1952.

[0100] Example 12 Compound 8

[0101] Compound 8 was synthesized using the method described in Example 5. The physicochemical properties of compound 8 are as follows:

[0102] 1) White solid;

[0103] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0104] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.62(d,J=6.8Hz,3H,-Ph,NH),8.17(t,J=9.6Hz,1H,-CH=CH-),8.11(d,J=2.0Hz,1H,-CH=CH-),7.99( d,J=6.8Hz,2H,-Ph),7.71(s,1H,-Ph),7.11(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.24(s ,2H,-CH2-),4.47(s,2H,-CH2-),3.41(d,J=6.8Hz,2H,-CH2-),3.27(s,2H,-CH2-),3.11(dd,J=6.0,12.4Hz,2H ,-CH2-),1.96(s,4H,-CH2-),1.40-1.48(m,2H,-CH2-),1.24-1.30(m,6H,-CH2-),0.87(t,J=6.4Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:164.9,163.3,156.1,152.2,149.0,148.4,148.0,145.9,144.3,143.2,136.0,134.4,131.3,126.3,122.7,122.6,12 0.0,119.0,117.0,114.8,114.7,107.7,100.0,73.3,60.5,31.5,30.6,29.3,29.0,26.6,26.5,24.7,22.6,14.5; HRMS(ESI)C 28 H 33 N2O5S[M-Br] + calcd=509.2105; found=509.211.

[0105] Example 13 Compound 9

[0106] Compound 9 was synthesized using the method described in Example 5. The physicochemical properties of compound 9 are as follows:

[0107] 1) Yellow solid;

[0108] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0109] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.62(d,J=7.2Hz,2H,-Ph),8.17(d,J=9.6Hz,1H,-CH=CH-),8.12(d,J=2.0Hz,1H,-CH=CH-),8.01(d,J=6.8Hz,2H,-Ph) ,7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-Ph),6.44(d,J=9.6Hz,1H,-CH=CH-),5.60(s,2H,-CH2-),4.48(d,J=5.60Hz,2H,-CH2- ),3.43(d,J=6.8Hz,2H,-CH2-),3.28(d,J=7.6Hz,2H,-CH2-),1.97(d,J=7.2Hz,4H,-CH2-),1.60-1.68(m,2H,-CH2-),1.43-1. 50(m,2H,-CH2-),1.34-1.40(m,2H,-CH2-),1.23-1.26(m,2H,-CH2-),0.96(t,J=7.2Hz,3H,-CH3),0.87(t,J=7.6Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.4,163.2,160.3,148.4,150.0,145.9,144.5,143.5,131.3,126.3,122.6,117.0,114.9,1 14.7,107.7,73.3,59.9,46.8,46.1,40.6,32.1,30.7,29.8,29.0,24.7,20.1,14.3,14.2; HRMS(ESI)C 30 H 37 N2O5S[M-Br] + calcd=537.2418; found=537.2427.

[0110] Example 14 Compound 10

[0111] Compound 10 was synthesized using the method described in Example 5. The physicochemical properties of compound 10 are as follows:

[0112] 1) Yellow solid;

[0113] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0114] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.63(d,J=7.2Hz,2H,-Ph),8.17(d,J=9.6Hz,1H,-CH=CH-),8.12(d,J=2.4Hz,1H,-CH=CH-),8.01(d,J=6 .8Hz,2H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.4Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.64(s,2H,-C H2-),4.48(t,J=5.6Hz,2H,-CH2-),3.43(t,J=6.4Hz,2H,-CH2-),3.17(t,J=6.8Hz,4H,-CH2-),2.51(t,J=2.0Hz ,2H,-CH-),1.92-2.07(m,6H,-CH-,-CH2-),0.95(d,J=6.4Hz,6H,-CH3),0.83(d,J=6.8Hz,6H,-CH3); HRMS(ESI)C 30 H 37 N2O5S[M-Br] + calcd=523.2261; found=523.2271.

[0115] Example 15 Compound 11

[0116] Compound 11 was synthesized using the method described in Example 5. The physicochemical properties of compound 11 are as follows:

[0117] 1) White solid;

[0118] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0119] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.62(d,J=6.4Hz,2H,-Ph),8.55(s,1H,NH),8.16(d,J=9.6Hz,1H,-CH=CH-),8.12(d,J=1.6Hz,1H ,-CH=CH-),7.97(d,J=6.4Hz,2H,-Ph),7.70(s,1H,-Ph),7.11(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6H z,1H,-CH=CH-),5.24(s,2H,-CH2-),4.42(t,J=6.0Hz,2H,-CH2-),3.13(dd,J=6.0,12.4Hz,2H,-CH2-),1 .68-1.89(m,6H,-CH2-),1.39-1.48(m,2H,-CH2-),1.28-1.37(m,2H,-CH2-),0.88(t,J=7.2Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:164.9,163.5,160.3,148.4,148.0,145.9,144.3,143.4,131.4,126.3,122.6, 117.0,114.7,107.7,73.8,60.4,31.5,30.9,29.5,27.7,25.0,20.0,14.2; HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=495.1948; found=495.1955.

[0120] Example 16 Compound 12

[0121] Compound 12 was synthesized using the method described in Example 5. The physicochemical properties of compound 12 are as follows:

[0122] 1) White solid;

[0123] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0124] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.62(t,J=7.6Hz,3H,-Ph,NH),8.16(d,J=9.6Hz,1H,-CH=CH-),8.12(d,J=2.0Hz,1H,-CH=CH-),7.96(d, J=6.4Hz,2H,-Ph),7.70(s,1H,-Ph),7.11(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.25(s,2H ,-CH2-),4.42(t,J=5.6Hz,2H,-CH2-),3.12(dd,J=6.4,12.4Hz,2H,-CH2-),1.77-1.90(m,4H,-CH2-),1.67-1.7 5(m,2H,-CH2-),1.45(t,J=6.4Hz,2H,-CH2-),1.20-1.35(m,2H,-CH2-),0.87(t,J=6.4Hz,3H,-CH3); HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=509.2105; found=509.2106.

[0125] Example 17 Compound 13

[0126] Compound 13 was synthesized using the method described in Example 5. The physicochemical properties of compound 13 are as follows:

[0127] 1) Yellow solid;

[0128] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0129] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.61(d,J=5.6Hz,2H,-Ph),8.56(t,J=5.6Hz,H,NH),8.16(d,J=9.6Hz,1H,-CH=CH-),8.12(d,J=2.0Hz,1H ,-CH=CH-),7.97(d,J=6.8Hz,2H,-Ph),7.70(s,1H,-Ph),7.11(d,J=2.4Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH =CH-),5.24(s,2H,-CH2-),4.42(t,J=6.0Hz,2H,-CH2-),3.12(dd,J=6.8,12.8Hz,2H,-CH2-),1.76-1.88(m,4H,- CH2-),1.66-1.75(m,2H,-CH2-),1.41-1.51(m,2H,-CH2-),1.09-1.40(m,8H,-CH2-),0.87(t,J=6.0Hz,3H,-CH3); 13 C NMR(100MHzDMSO)δ:164.9,163.5,160.3,148.4,148.0,145.8,144.3,143.5,131.5,126.3,122.7, 117.0,114.7,107.7,73.8,60.5,31.5,31.0,29.5,29.4,27.7,26.5,25.0,22.6,14.4; HRMS(ESI)C 29 H 35 N2O5S[M-Br] + calcd=523.2261; found=523.2264.

[0130] Example 18 Compound 14

[0131] Compound 14 was synthesized using the method described in Example 5. The physicochemical properties of compound 14 are as follows:

[0132] 1) Yellow solid;

[0133] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0134] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.61(d,J=5.2Hz,2H,-Ph),8.17(d,J=9.6Hz,1H,-CH=CH-),8.13(d,J=2.0Hz,1H,-CH=CH-),7.99(d,J =7.2Hz,2H,-Ph),7.70(s,1H,-Ph),7.11(d,J=2.4Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.62(s,2H ,-CH2-),4.43(t,J=6.0Hz,2H,-CH2-),3.29(t,J=7.2Hz,2H,-CH2-),1.77-1.89(m,4H,-CH2-),1.66-1.77(m,2 H,-CH2-),1.60-1.78(m,2H,-CH2-),1.19-1.52(m,8H,-CH2-),0.92(dt,J=7.2,36.0Hz,6H,-CH3); HRMS(ESI)C 31 H 39 N2O5S[M-Br] + calcd=551.2574; found=551.2587.

[0135] Example 19 Compound 15

[0136] Compound 15 was synthesized using the method described in Example 5. The physicochemical properties of compound 15 are as follows:

[0137] 1) Yellow liquid;

[0138] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0139] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO) δ: 8.61 (d, J = 6.8 Hz, 2H, -Ph), 8.16 (d, J = 9.6 Hz, 1H, -CH = CH-), 8.12 (d, J = 2.0 Hz, 1H, -CH = CH-), 7.98 (d, J = 6. 8Hz,2H,-Ph),7.70(s,1H,-Ph),7.11(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.62(s,2H,-CH2- ),4.42(t,J=6.0Hz,2H,-CH2-),3.36(s,2H,-CH2-),3.17(t,J=6.4Hz,4H,-CH2-),1.94-2.08(m,2H,-CH-),1.77-1 .90(m,4H,-CH2-),1.69-1.76(m,2H,-CH2-),0.95(d,J=6.4Hz,6H,-CH3),0.83(d,J=6.8Hz,6H,-CH3); HRMS(ESI)C 31 H 39 N2O5S[M-Br] + calcd=551.2574; found=551.2584.

[0140] Example 20 Compound 16

[0141] Compound 16 was synthesized using the method described in Example 5. The physicochemical properties of compound 16 are as follows:

[0142] 1) White liquid;

[0143] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0144] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.93(d,J=5.2Hz,1H,-Ph),8.74(t,J=5.2Hz,1H,NH),8.45-8.55(m,1H,-Ph),8.25(d,J=8.0Hz,1H,-Ph),8.18(d,J= 9.6Hz,1H,-CH=CH-),8.14(d,J=2.4Hz,1H,-CH=CH-),7.87(m,1H,-Ph),7.73(s,1H,-Ph),7.13(d,J=2.0Hz,1H,-CH=CH-),6.4 6(d,J=9.6Hz,1H,-CH=CH-),5.39(s,2H,-CH2-),4.53(t,J=5.6Hz,2H,-CH2-),3.72(t,J=7.2Hz,2H,-CH2-),3.07(t,J=5.6H z,2H,-CH2-),2.19(t,J=6.8Hz,2H,-CH2-),1.34-1.40(m,2H,-CH2-),1.24-1.28(m,2H,-CH2-),0.82(t,J=7.2Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.5,160.3,160.0,148.6,148.4,147.7,145.8,144.7,143.3,131.1,126.4,126.2, 123.0,117.0,115.0,114.7,107.7,72.1,60.4,32.1,31.4,29.7,28.8,19.9,14.0; HRMS(ESI)C 25 H 27 N2O5S[M-Br] + calcd=467.1635; found=467.1644.

[0145] Example 21 Compound 17

[0146] Compound 17 was synthesized using the method described in Example 5. The physicochemical properties of compound 17 are as follows:

[0147] 1) Yellow liquid;

[0148] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0149] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.91(d,J=5.6Hz,1H,-Ph),8.64(t,J=5.6Hz,1H,NH),8.40-8.50(m,1H,-Ph),8.25(d,J=8.0Hz,1H,-Ph),8.18(d ,J=9.6Hz,1H,-CH=CH-),8.13(d,J=2.0Hz,1H,-CH=CH-),7.88(t,J=6.4Hz,1H,-Ph),7.73(s,1H,-Ph),7.13(d,J=2.0Hz, 1H,-CH=CH-),6.47(d,J=9.6Hz,1H,-CH=CH-),5.37(s,2H,-CH2-),4.53(t,J=5.6Hz,2H,-CH2-),3.72(t,J=7.2Hz,2H,-C H2-),2.16-2.23(m,2H,-CH2-),1.39(t,J=6.4Hz,2H,-CH2-),1.23(t,J=7.2Hz,2H,-CH2-),0.82(t,J=6.8Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.4,160.3,159.6,148.6,148.5,147.7,145.9,144.8,143.3,131.1,126.4,126.2, 123.0,117.0,115.0,114.8,107.7,72.1,60.3,32.1,30.0,29.0,28.8,22.2,14.4; HRMS(ESI)C 26 H 29 N2O5S[M-Br] + calcd=481.1792; found=481.1799.

[0150] Example 22 Compound 18

[0151] Compound 18 was synthesized using the method described in Example 5. The physicochemical properties of compound 18 are as follows:

[0152] 1) Orange liquid;

[0153] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0154] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.92(d,J=5.6Hz,1H,-Ph),8.67(t,J=5.6Hz,1H,NH),8.49(t,J=8.4Hz,1H,-Ph),8.26(d,J=8.4Hz,1H,-Ph),8.19(d,J=9 .6Hz,1H,-CH=CH-),8.13(d,J=2.0Hz,1H,-CH=CH-),7.88(t,J=7.2Hz,1H,-Ph),7.73(s,1H,-Ph),7.13(d,J=2.0Hz,1H,-CH=CH-), 6.46(d,J=9.6Hz,1H,-CH=CH-),5.38(s,2H,-CH2-),4.53(t,J=5.6Hz,2H,-CH2-),3.72(t,J=7.2Hz,2H,-CH2-),3.07(dd,J=6.4,1 2.4Hz,2H,-CH2-),2.19(t,J=6.4Hz,2H,-CH2-),1.35-1.40(m,2H,-CH2-),1.21-1.26(m,6H,-CH2-),0.82(t,J=6.8Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.4,160.3,160.0,148.6,148.5,147.7,145.9,144.8,143.3,131.1,126.3,126.2,123 .0,117.0,115.0,114.8,107.7,72.0,60.3,31.4,30.0,29.3,28.8,26.4,22.5,14.4; HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=495.1948; found=495.1952.

[0155] Example 23 Compound 19

[0156] Compound 19 was synthesized using the method described in Example 5. The physicochemical properties of compound 19 are as follows:

[0157] 1) Yellow liquid;

[0158] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0159] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.91(d,J=6.4Hz,1H,-Ph),8.51(t,J=8.0Hz,1H,-Ph),8.30(d,J=8.4Hz,1H,-Ph),8.19(d,J=9.6Hz,1H,-CH=CH-),8. 12(d,J=2.0Hz,1H,-CH=CH-),7.90(t,J=6.8Hz,1H,-Ph),7.74(s,1H,-Ph),7.13(d,J=2.0Hz,1H,-CH=CH-),6.46(d,J=9.6Hz,1 H,-CH=CH-),5.69(s,2H,-CH2-),4.50(t,J=5.6Hz,2H,-CH2-),3.75(t,J=6.8Hz,2H,-CH2-),3.18(t,J=7.2Hz,2H,-CH2-),2. 14-2.24(m,2H,-CH2-),1.52-1.60(m,2H,-CH2-),1.15-1.43(m,8H,-CH2-),0.84(dt,J=7.2Hz,44.0Hz,6H,-CH3); HRMS(ESI)C 29 H 35 N2O5S[M-Br] + calcd=523.2261; found=523.2270.

[0160] Example 24 Compound 20

[0161] Compound 20 was synthesized using the method described in Example 5. The physicochemical properties of compound 20 are as follows:

[0162] 1) Yellow liquid;

[0163] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0164] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.91(d,J=5.6Hz,1H,-Ph),8.52(t,J=8.4Hz,1H,-Ph),8.30(d,J=8.8Hz,1H,-Ph),8.19(d,J=9.6Hz,1H,-CH=CH-), 8.13(d,J=2.0Hz,1H,-CH=CH-),7.90(t,J=6.8Hz,1H,-Ph),7.73(s,1H,-Ph),7.14(d,J=2.0Hz,1H,-CH=CH-),6.47(d,J=9. 6Hz,1H,-CH=CH-),5.71(s,2H,-CH2-),4.52(t,J=5.6Hz,2H,-CH2-),3.74(t,J=7.2Hz,2H,-CH2-),3.16(d,J=7.2Hz,2H,-C H2-),3.07(d,J=7.2Hz,2H,-CH2-),2.13-2.23(m,2H,-CH2-),1.88-1.89(m,2H,-CH-),0.83(dd,J=6.4,58.0Hz,12H,-CH3); 13 C NMR(100MHz DMSO)δ:163.8,160.2,160.0,148.6,148.4,147.8,145.9,145.0,143.3,131.2,126.8,126.4,123.4 ,117.0,115.0,114.8,107.7,72.1,60.1,54.4,53.5,32.1,28.8,27.4,26.4,20.4,20.2; HRMS(ESI)C 29 H 35 N2O5S[M-Br] + calcd=523.2261; found=523.2272.

[0165] Example 25 Compound 21

[0166] Compound 21 was synthesized using the method described in Example 5. The physicochemical properties of compound 21 are as follows:

[0167] 1) White liquid;

[0168] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0169] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.90(d,J=6.0Hz,1H,-Ph),8.67(t,J=5.6Hz,1H,NH),8.44(t,J=7.6Hz,1H,-Ph),8.14-8.22(m,2H,-Ph,-CH=CH-), 8.11(d,J=2.4Hz,1H,-CH=CH-),7.86(t,J=6.8Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6 Hz,1H,-CH=CH-),5.37(s,2H,-CH2-),4.46(t,J=5.6Hz,2H,-CH2-),3.58(t,J=6.0Hz,2H,-CH2-),3.14(dd,J=6.4,12.4Hz,2 H,-CH2-),1.95(s,4H,-CH2-),1.39-1.47(m,2H,-CH2-),1.28-1.35(m,2H,-CH2-),0.86(t,J=7.2Hz,3H,-CH3); HRMS(ESI)C 26 H 29 N2O5S[M-Br] + calcd=481.1792; found=481.1799.

[0170] Example 26 Compound 22

[0171] Compound 22 was synthesized using the method described in Example 5. The physicochemical properties of compound 22 are as follows:

[0172] 1) Yellow liquid;

[0173] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0174] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.90(d,J=6.0Hz,1H,-Ph),8.68(t,J=5.2Hz,1H,NH),8.44(t,J=7.2Hz,1H,-Ph),8.15-8.21(m,2H,-Ph,-CH=CH-),8 .11(d,J=2.0Hz,1H,-CH=CH-),7.86(t,J=6.8Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz ,1H,-CH=CH-),5.37(s,2H,-CH2-),4.45(t,J=5.2Hz,2H,-CH2-),3.58(t,J=6.4Hz,2H,-CH2-),3.13(dd,J=6.4,12.4Hz,2H,- CH2-),1.95(d,J=2.8Hz,4H,-CH2-),1.44(t,J=6.8Hz,2H,-CH2-),1.26(t,J=3.6Hz,4H,-CH2-),0.83(t,J=6.8Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.5,160.3,160.0,148.5,148.4,147.9,145.9,144.6,143.4,131.3,126.3,126.2,122 .8,117.0,114.8,114.7,107.7,100.0,73.2,60.3,32.6,29.0,28.8,24.7,22.3,14.4; HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=495.1948; found=495.1957.

[0175] Example 27 Compound 23

[0176] Compound 23 was synthesized using the method described in Example 5. The physicochemical properties of compound 23 are as follows:

[0177] 1) Yellow liquid;

[0178] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0179] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.90(d,J=6.0Hz,1H,-Ph),8.68(t,J=5.2Hz,1H,NH),8.44(t,J=8.4Hz,1H,-Ph),8.18(t,J=6.0Hz,2H,-Ph,-CH=CH -),8.11(d,J=2.4Hz,1H,-CH=CH-),7.86(t,J=6.8Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J= 9.6Hz,1H,-CH=CH-),5.37(s,2H,-CH2-),4.45(t,J=5.2Hz,2H,-CH2-),3.58(d,J=5.6Hz,2H,-CH2-),3.13(dd,J=6.4,12.4 Hz,2H,-CH2-),1.95(d,J=3.2Hz,4H,-CH2-),1.43(t,J=6.0Hz,2H,-CH2-),1.23(s,6H,-CH2-),0.81(t,J=6.4Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.5,160.3,159.8.0,148.5,148.4,147.9,145.9,144.6,143.4,131.3,126.3,122.8,117. 0,114.8,114.7,107.7,100.0,73.2,60.3,32.6,31.4,29.3,28.8,26.5,24.7,22.6,14.4; HRMS(ESI)C 28 H 33 N2O5S[M-Br] + calcd=509.2015; found=509.2112.

[0180] Example 28 Compound 24

[0181] Compound 24 was synthesized using the method described in Example 5. The physicochemical properties of compound 24 are as follows:

[0182] 1) White solid;

[0183] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0184] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.91(d,J=67.6Hz,1H,-Ph),8.47(t,J=8.0Hz,1H,-Ph),8.23(d,J=8.0Hz,1H,-Ph),8.17(d,J=9.6Hz,1H,-CH= CH-),8.11(s,1H,-CH=CH-),7.88(t,J=6.8Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(s,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,- CH=CH-),5.70(s,2H,-CH2-),4.46(s,2H,-CH2-),3.59(s,2H,-CH2-),3.28(t,J=7.6Hz,4H,-CH2-),1.95(s,4H,-CH2-) ,1.63(d,J=6.0Hz,2H,-CH2-),1.34-1.48(m,2H,-CH2-),1.21-1.25(m,2H,-CH2-),0.84(dt,J=7.2,44.8Hz,6H,-CH3); 13 C NMR(100MHz DMSO)δ:163.0,160.3,160.0,148.4,147.9,145.9,144.8,143.4,131.3,126.7,126.3,123.2,11 7.0,114.8,107.7,73.2,59.9,46.9,46.1,32.9,30.8,29.7,28.8,24.7,20.0,14.2; HRMS(ESI)C 30 H 37 N2O5S[M-Br] / 1 + calcd=537.2418;found=537.2427.HRMS(ESI)C 30 H 37 N2O5S[M-Br] + calcd=537.2418; found=537.2426.

[0185] Example 29 Compound 25

[0186] Compound 25 was synthesized using the method described in Example 5. The physicochemical properties of compound 25 are as follows:

[0187] 1) Yellow liquid;

[0188] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0189] With DMSO as solvent, the peaks are attributed to: 1 H NMR(400MHz DMSO)δ:8.92(d,J=5.6Hz,1H,-Ph),8.47(t,J=7.2Hz,1H,-Ph),8.22(d,J=8.4Hz,1H,-Ph),8.17(d,J=9.6Hz,1H,-CH=CH- ),8.11(d,J=2.4Hz,1H,-CH=CH-),7.88(t,J=6.4Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d, J=9.6Hz,1H,-CH=CH-),5.72(s,2H,-CH2-),4.45(t,J=5.6Hz,2H,-CH2-),3.58(t,J=6.0Hz,2H,-CH2-),3.18(dd,J=7.2, 26.4Hz,4H,-CH2-),1.87-2.03(m,6H,-CH-,-CH2-),0.96(d,J=6.4Hz,6H,-CH3),0.81(d,J=6.8Hz,6H,-CH3); HRMS(ESI)C 29 H 35 N2O5S[M-Br] + calcd=523.2261; found=523.2272.

[0190] Example 30 Compound 26

[0191] Compound 26 was synthesized using the method described in Example 5. The physicochemical properties of compound 26 are as follows:

[0192] 1) White solid;

[0193] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0194] With DMSO as solvent, the peaks are attributed to: 1H NMR(400MHz DMSO)δ:8.89(d,J=5.6Hz,1H,-Ph),8.68(t,J=5.2Hz,1H,NH),8.44(t,J=7.6Hz,1H,-Ph),8.13-8.19(m,2H,-Ph,-CH=CH-),8.11( d,J=2.0Hz,1H,-CH=CH-),7.85(t,J=6.8Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.4Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH =CH-),5.37(s,2H,-CH2-),4.40(t,J=6.0Hz,2H,-CH2-),3.49(t,J=6.8Hz,2H,-CH2-),3.13(dd,J=6.4,12.4Hz,2H,-CH2-),1.75 -1.88(m,4H,-CH2-),1.65-1.73(m,2H,-CH2-),1.38-1.44(m,2H,-CH2-),1.26-1.33(m,4H,-CH2-),0.84(t,J=7.2Hz,3H,-CH3); 13 C NMR(100MHz DMSO)δ:163.5,160.3,159.9,148.5,148.4,148.0,145.9,144.6,143.4,131.4,126.3,126.2, 122.8,117.0,114.7,107.7,73.8,60.2,32.9,31.4,29.4,27.6,24.9,20.0,14.1; HRMS(ESI)C 27 H 31 N2O5S[M-Br] + calcd=495.1948; found=495.1953.

[0195] Example 31 Compound 27

[0196] Compound 27 was synthesized using the method described in Example 5. The physicochemical properties of compound 27 are as follows:

[0197] 1) White solid;

[0198] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0199] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.89(d,J=6.4Hz,1H,-Ph),8.69(t,J=4.8Hz,1H,NH),8.44(t,J=7.6Hz,1H,-Ph),8.13-8.20(m,2H,-Ph,-CH=CH-),8.11(d, J=2.0Hz,1H,-CH=CH-),7.85(t,J=6.8Hz,1H,-Ph),7.70(s,1H,-Ph),7.11(d,J=2.4Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-) ,5.36(s,2H,-CH2-),4.40(t,J=6.0Hz,2H,-CH2-),3.49(t,J=6.8Hz,2H,-CH2-),3.12(dd,J=6.4,12.0Hz,2H,-CH2-),1.75-1.86(m ,4H,-CH2-),1.65-1.73(m,2H,-CH2-),1.39-1.46(m,2H,-CH2-),1.22-1.26(m,2H,-CH2-),0.84(t,J=6.8Hz,3H,-CH3); HRMS(ESI)C 28 H 33 N2O5S[M-Br] + calcd=509.2105; found=509.2111.

[0200] Example 32 Compound 28

[0201] Compound 28 was synthesized using the method described in Example 5. The physicochemical properties of compound 28 are as follows:

[0202] 1) White solid;

[0203] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0204] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.89(d,J=6.0Hz,1H,-Ph),8.65(t,J=4.8Hz,1H,NH),8.44(t,J=8.4Hz,1H,-Ph),8.13-8.20(m,2H,-Ph,-CH=CH-),8.11(d, J=2.4Hz,1H,-CH=CH-),7.85(t,J=7.2Hz,1H,-Ph),7.71(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-) ,5.36(s,2H,-CH2-),4.40(t,J=6.0Hz,2H,-CH2-),3.49(t,J=6.8Hz,2H,-CH2-),3.12(dd,J=6.4,12.4Hz,2H,-CH2-),1.76-1.87(m ,4H,-CH2-),1.65-1.73(m,2H,-CH2-),1.38-1.46(m,2H,-CH2-),1.20-1.27(m,6H,-CH2-),0.81(t,J=6.4Hz,3H,-CH3); HRMS(ESI)C 29 H 35 N2O5S[M-Br] + calcd=523.2261; found=523.2266.

[0205] Example 33 Compound 29

[0206] Compound 29 was synthesized using the method described in Example 5. The physicochemical properties of compound 29 are as follows:

[0207] 1) Yellow liquid;

[0208] 2) The NMR spectrum of the compound ( 1 H NMR, 500 MHz) characteristics:

[0209] With CDCl3 as solvent, the peaks are attributed to: 1H NMR(500MHz CDCl3) δ: 9.63 (d, J = 4.0Hz, 1H, -Ph), 8.25 (t, J = 7.5Hz, 1H, -Ph), 7.90 (d, J = 8.5Hz, 1H, -Ph), 7.82 (d, J = 10.0Hz, 2H, -CH = CH-), 7.71 (d, J = 2.0Hz ,1H,-CH=CH-),7.63(s,1H,-Ph),7.41(s,1H,-Ph),6.84(d,J=1.5Hz,1H,-CH=CH-),6.38(d,J=9.5Hz,1H,-CH=CH-),6.38(s,2H,-CH2-),4.49(t ,J=5.5Hz,2H,-CH2-),3.46(t,J=7.5Hz,2H,-CH2-),3.40(t,J=7.0Hz,2H,-CH2-),3.33(t,J=7.5Hz,2H,-CH2-),1.86-1.20(m,6H,-CH2-),1.70 HRMS(ESI)C 31 H 39 N2O5S[M-Br] + calcd=551.25741; found=551.2582.

[0210] Example 34 Compound 30

[0211] Compound 30 was synthesized using the method described in Example 5. The physicochemical properties of compound 30 are as follows:

[0212] 1) Yellow liquid;

[0213] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0214] DMSO was used as solvent, and the peaks were attributed to: 1H NMR(400MHz DMSO)δ:8.91(d,J=6.4Hz,1H,-Ph),8.47(t,J=8.8Hz,1H,-Ph),8.18-8.27(m,2H,-Ph,-CH=CH-),8.11(d,J=2.0Hz,1H,-CH=CH- ),7.87(t,J=7.2Hz,1H,-Ph),7.70(s,1H,-Ph),7.12(d,J=2.0Hz,1H,-CH=CH-),6.44(d,J=9.6Hz,1H,-CH=CH-),5.71(s,2H,-CH 2-),4.39(t,J=6.0Hz,2H,-CH2-),3.50(t,J=7.2Hz,2H,-CH2-),3.20(dd,J=6.8,14.0Hz,2H,-CH2-),1.88-2.08(m,4H,-CH2-,- HRMS(ESI)C 31 H 39 N2O5S[M-Br] + calcd=551.25741; found=551.2581.

[0215] Application Example 1: In vitro antibacterial activity assay

[0216] 1. Test bacteria:

[0217] Staphylococcus aureus (Staphylococcus aureus ATCC 29213); Escherichia coli (Escherichiacoli ATCC25922); Methicillin-resistant Staphylococcus aureus (MRSA).

[0218] 2. Samples and reagents:

[0219] The samples were: vancomycin, meropenem and compound 1-30 prepared in the examples.

[0220] 3. Test method:

[0221] According to the standards of the Clinical Laboratory Standards Institute (CLSI), the in vitro antibacterial activities of compounds 1-30 prepared according to the present invention and the clinical antibacterial drug vancomycin were tested using a serial dilution method in a 96-well plate. The drug concentration observed in the smallest completely clear well by naked eye was defined as the MIC value.

[0222] Table 1. MIC values of the pyridinium quaternary ammonium salt-containing Zanthoxylum bungeanum ether derivatives 1-30 prepared by the present invention against 10 MRSA clinical isolates

[0223]

[0224]

[0225] a Sa: Staphylococcus aureus (S. aureus ATCC 29213); b N315: MSRA clinical standard strain: c M(13, 16-17, 20-23): 9 clinical isolates of MRSA; d Ec: Escherichia coli ATCC 25922; e SI: selectivity index (HC 50 / MICs of S. aureus); f Van: Vancomycin; h MEM: Meropenem; g ND: not detected. The experiment was repeated at least 3 times.

[0226] It can be concluded from Table 1 that the zanthoxylum toxin ether derivatives containing pyridinium quaternary ammonium salt prepared by the present invention have good antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Except for compounds 12 and 24, the other derivatives all show better antibacterial activity than the parent compound, especially compound 13, which has the best antibacterial effect, with an MIC value of 1-2 μg / mL, close to that of the positive drug vancomycin, and has relatively stable antibacterial activity against 10 clinically isolated MRSA strains. Therefore, it is expected to become a clinical antibacterial drug for methicillin-resistant Staphylococcus aureus.

[0227] Application Example 2: Time-killing kinetics experiment of compound 27:

[0228] 1. Test bacteria:

[0229] Staphylococcus aureus ATCC 29213; MRSA N315 (clinical standard strain).

[0230] 2. Samples and reagents:

[0231] The samples were: vancomycin and compound 13 prepared in Example.

[0232] 3. Test method:

[0233] Single colonies of Staphylococcus aureus and MRSA N315 were picked and placed in 1 mL of MHB liquid medium and cultured in a shaker (200 rpm, 37°C) for 16-18 hours. The bacterial solution was then diluted 10,000 times with LB liquid medium and cultured for another 2.5 hours. The bacterial solution was diluted to 1×10 5 cfu / mL. Then, different concentrations of compound 27 (4×, 8×MIC) were added to the bacterial solution, and vancomycin (8×MIC) was used as a positive control, and a blank group without drug addition was set up. The culture was continued in a shaker (200rpm, 37°C). 100μL of each group was taken at each time point of 0h, 0.5h, 1h, 2h, 4h, 6h, and 8h after drug addition. The cells were centrifuged at 3500rpm and 4°C for 3min, the supernatant was removed, and the cells were washed three times. The cells were resuspended with 100μL of 1×PBS buffer solution, diluted in multiple ratios, and counted on drop plates. Three parallel controls were set up for each group. The cells were cultured overnight in a 37°C constant temperature incubator. The number of colonies was counted the next day. The unit was log 10 cfu / mL, plot, the results are as follows Figure 1 As shown in A and B.

[0234] Staphylococcus aureus and MRSA clinical standard strain N315 were respectively selected into 1 mL of MHB broth and cultured overnight in a shaker at 37°C and 200 rpm. The bacterial solution was then diluted and shaken for 2.5 hours to obtain a concentration of 1×10 5 cfu / mL of bacterial solution (early exponential period). Continue culturing to obtain a concentration of 1×10 7 cfu / mL of bacterial solution (late exponential phase). Test compound and vancomycin were added to 1×10 5 cfu / mL / 1×10 7 The cfu / mL bacterial solution was prepared into 4×, 8× and 8×MIC respectively, and the pure bacterial solution was used as the Control group and continued to be shaken and cultured. At different time points (0, 0.5, 1, 2, 4, 6, 8, 10, 12h), 100μL of bacterial solution was aspirated and centrifuged at 500rpm and 4°C. The supernatant was slowly aspirated, and the bacteria were washed and resuspended three times with PBS buffer. Gradient dilution was performed, and the resuspended bacterial solution of different concentrations was dropped onto the surface of the MHA solid culture medium. The bacterial solution was dried and inverted in a 37°C incubator for 12-16h. The number of colonies was observed and recorded. Three parallels were set for each concentration, and the experiment was repeated at least three times. The time-killing kinetic curve was drawn according to the bacterial concentration and the number of colonies at different time points. The unit is log 10 cfu / mL, plot, the results are as follows Figure 1 As shown in A, B, C, and D.

[0235] Figure 1A, B, C, and D show that for S. aureus in the early exponential phase, compound 13 at 4× and 8× the MIC killed 60% of the bacteria within 2 hours and inhibited further growth, while the anti-inflammatory drug vancomycin required 8 hours to achieve complete inhibition. For S. aureus in the late exponential phase, compound 13 at 8× the MIC killed 70% of the bacteria within 8 hours and inhibited further growth, while compound 13 at 4× the MIC and vancomycin failed to inhibit growth. Similarly, for MRSAN315 in the early exponential phase, compound 13 at 8× the MIC completely inhibited its growth within 2 hours, while compound 13 at 4× the MIC and the anti-inflammatory drug vancomycin required 8 hours to achieve complete inhibition. For S. aureus in the late exponential phase, compound 13 at 8× the MIC completely inhibited its growth within 12 hours, while compound 13 at 4× the MIC and vancomycin failed to inhibit bacterial growth. Therefore, compared with the positive drug vancomycin, compound 13 can kill bacteria more quickly and inhibit bacterial growth in a concentration-dependent manner, and is expected to be developed into a clinical rapid antibacterial drug. Application Example 3: Drug resistance induction experiment of compound 13:

[0236] First, the MIC of the compound and norfloxacin against Staphylococcus aureus was determined. Then, an MHA solid culture medium containing sub-inhibitory concentrations of the target compound 13 and norfloxacin was prepared. Single colonies of Staphylococcus aureus were picked and cultured in MHB broth containing 1 / 2×MIC of the test compound and norfloxacin for 12 hours, and the bacterial liquid was inoculated onto the surface of the MHA solid culture medium containing sub-inhibitory concentrations of the target compound and norfloxacin, and cultured in a 37°C incubator for 12 hours. The MIC of compound 13 and norfloxacin against the cultured Staphylococcus aureus was determined, and the above operation was repeated, and the MIC values were continuously subcultured for a total of 20 generations. The results are shown in FIG. Figure 2 .

[0237] from Figure 2 The results showed that the MIC value of norfloxacin first increased on the third day and gradually increased over time, reaching 128 μg / mL on the 18th day, indicating that norfloxacin can induce drug resistance in Staphylococcus aureus. However, the MIC value of compound 13 against Staphylococcus aureus (S. aureus ATCC 29213) remained basically stable over 20 days, indicating that compound 13 did not induce drug resistance in bacteria.

[0238] Application Example 4: In vivo safety evaluation experiment

[0239] 1. Reagents:

[0240] Compound 13 prepared in Example, 0.9% NaCl.

[0241] 2. Test animals

[0242] SPF grade KM mice (purchased from Beijing Sibeifu Biotechnology Co., Ltd., body weight 19-22 g, 4-6 weeks old).

[0243] 3. Test methods

[0244] 30 healthy Kunming mice of the same weight were selected and randomly divided into 6 groups (blank group, 40, 20, 10, 5 mg / kg), with 5 mice in each group. The mice were ear-tagged, the hair on the back of the mice was shaved with a shaver, and then a depilatory cream was used to remove the remaining stubborn hair. After 24 hours of feeding, 60 μL of the corresponding compound solution was injected into the back skin of the mice, and the blank group was injected with an equal volume of 0.9% NaCl solution. The mice were observed within 24 hours to see if there were any adverse reactions such as death, skin redness, swelling, and ulceration. The mice in the largest drug-dosing group without any adverse reactions were selected for eye blood sampling. The processed whole blood and serum were sent for routine blood tests and blood biochemistry tests respectively to evaluate whether compound 13 was toxic to mice in vivo. The results are as follows: Figure 3 shown.

[0245] By subcutaneously injecting mice with different concentrations of the compound, it was found that when the concentration of compound 13 was ≤20 mg / kg, the mice did not show any adverse reactions on the skin (such as redness, swelling, hardening, ulceration, etc.). Therefore, routine blood tests and blood biochemical index tests were performed on the mice at this dosage. Therefore, we selected mice dosed with 20 mg / kg for routine blood tests [white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), platelet count (PLT) and mean corpuscular volume (MCV)] and blood biochemistry [alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea (UREA) and creatinine (CREA)]. Figure 3 It was found that compared with the Control group (0.9% NaCl), there was no significant difference in the ten indicators of KM mice after subcutaneous injection of compound 13 (20 mg / kg). The results showed that compound 13 has certain in vivo safety.

[0246] Application Example 5: In vivo anti-MRSA infection activity experiment of compound 13

[0247] 1. Test bacteria:

[0248] MRSA N315 (clinical isolate)

[0249] 2. Samples and reagents:

[0250] The samples were: vancomycin, compound 13 prepared in Example, and 0.9% NaCl.

[0251] 3. Test animals:

[0252] SPF grade KM mice (purchased from Beijing Sibeifu Biotechnology Co., Ltd., body weight 19-22 g, 4-6 weeks old).

[0253] 4. Test method:

[0254] Thirty healthy female Kunming mice of the same weight were randomly divided into five groups, each with six mice, namely, blank group, model group, positive control group (vancomycin 5 mg / kg), low-concentration group of compound 13 (5 mg / kg), and high-concentration group of compound 13 (10 mg / kg). Except for the blank group, 60 μL of bacterial solution (1×10 8 cfu / mL) for modeling, and the blank group was injected with an equal volume of saline. 2 hours later, different groups were injected with 60μL of different drugs for treatment, and the blank group and model group were injected with an equal volume of saline. The mice were observed for 24 hours, and the survival rate and back skin infection status of the mice were recorded. The mice were sacrificed, the infected skin was cryogenically ground, and then the supernatant was centrifuged and counted on a drop plate. The skin bacterial load of the mice was read after 24 hours. The results are as follows. Figure 4 shown.

[0255] The results showed that compared with the model group, treatment with vancomycin (5 mg / kg) and 13 (5 mg / kg) reduced the bacterial load on the mouse skin by 88.410% (0.948 log CFU / g) and 94.563% (1.275 log CFU / g), respectively. Furthermore, treatment with 13 (10 mg / kg) reduced the bacterial load on the mouse skin by 99.661% (2.773 log CFU / g). This confirms that the pyridine-containing quaternary ammonium salt of zanthoxylum toxin ether 13 has a good therapeutic effect on MRSA-infected mouse skin abscesses, outperforming the control drug vancomycin and showing promise as an anti-MRSA drug.

Claims

1. A pyridine-containing Zanthoxylum bungeanum toxin ether derivative or a pharmaceutically acceptable salt thereof, the structure of which is shown in the following formula (I): in, n=3, 4 or 5, R1 and R2 are independently selected from H or C2-C8 alkyl.

2. The pyridine-containing zanthoxylum bungeanum ether derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the formula (I), Located at the ortho or para position of the N atom on the pyridine group, said R1 and R2 are independently selected from H or C4-C6 alkyl.

3. The pyridine-containing zanthoxylum bungeanum ether derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the formula (I), When located in the para position relative to the nitrogen atom of the pyridine group, n, R1 and R2 are (1) to (15) in the following combinations, When located in the ortho position of the nitrogen atom on the pyridine group, n, R1 and R2 are (16)-(30) in the following combinations: (1) n = 3, R1 = H, R2 = -CH2CH2CH2CH3; (2) n = 3, R1 = H, R2 = -CH2CH2CH2CH2CH3; (3) n = 3, R1 = H, R2 = -CH2CH2CH2CH2CH2CH3; (4) n = 3, R1 = R2 = -CH2CH2CH2CH3; (5) n = 3, R1 = R2 = -CH2CH(CH3)2; (6) n = 4, R1 = H, R2 = -CH2CH2CH2CH3; (7) n = 4, R1 = H, R2 = -CH2CH2CH2CH2CH3; (8) n = 4, R1 = H, R2 = -CH2CH2CH2CH2CH2CH3; (9) n =4, R1 = R2 = -CH2CH2CH2CH3(10) n = 4, R 1 = R 2 = -CH2CH(CH3)2; (11) n = 5, R1 = H, R2 = -CH2CH2CH2CH3; (12) n = 5, R1 = H, R2 = -CH2CH2CH2CH2CH3; (13) n = 5, R2 = -CH2CH2CH2CH2CH2CH3; (14) n = 5, R1 = R2 = -CH2CH2CH2CH3; (15) n = 5, R1 = R2 = -CH2CH(CH3)2; (16) n = 3, R1 = H, R2 = -CH2CH2CH2CH3; (17) n = 3, R1 = H, R2 = -CH2CH2CH2CH2CH3; (18) n = 3, R1 = H, R2 = -CH2CH2CH2CH2CH2CH3; (19) n = 3, R1 = R2 = -CH2CH2CH2CH3; (20) n = 3, R1 = R2 = -CH2CH(CH3)2; (21) n = 4, R1 = H, R2 = -CH2CH2CH2CH3; (22) n = 4, R1 = H, R2 = -CH2CH2CH2CH2CH3; (23) n = 4, R1 = H, R2 = -CH2CH2CH2CH2CH2CH3; (24) n =4, R1 = R2 = -CH2CH2CH2CH3;(25) n = 4, R 1 = R 2 = -CH2CH(CH3)2; (26) n = 5, R1 = H, R2 = -CH2CH2CH2CH3; (27) n = 5, R1 = H, R2 = -CH2CH2CH2CH2CH3; (28) n = 5, R2 = -CH2CH2CH2CH2CH2CH3; (29) n = 5, R1 = R2 = -CH2CH2CH2CH3; (30) n = 5, R1 = R2 = -CH2CH(CH3)2.

4. The pyridine-containing Zanthoxylum bungeanum ether derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt of the pyridine-containing zanthoxylin ether derivative is selected from bromide, chloride or iodide. Preferably, the pharmaceutically acceptable salt of the pyridine-containing zanthoxylin ether derivative is a bromide, and its structure is shown below:

5. The method for preparing the pyridine-containing Zanthoxylum bungeanum ether derivative according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Using Zanthoxylum bungeanum toxin as a substrate, the methoxy group is converted into a phenolic hydroxyl group under the action of a demethylation reagent to obtain intermediate a; (2) Intermediate a reacts with different dibromoalkanes under alkaline conditions to synthesize intermediate b; (3) Intermediate b reacts with mercaptopyridine under alkaline conditions to generate intermediate c; (4) Intermediate c then reacts with intermediate d to generate the pyridine-containing zanthoxylum bungeanum ether derivative, as shown in the following reaction formula: Wherein, R1, R2 and n are the same as those described in any one of claims 1-4, and R3 is selected from Br, Cl or I.

6. The method for preparing the pyridine-containing Zanthoxylum bungeanum ether derivative according to claim 5, characterized in that: In step (1), the demethylation agent is selected from boron tribromide, the reaction molar ratio of the zanthoxylum toxin to boron tribromide is 1:3-1:6, the reaction temperature is 0°C, and the reaction solvent is anhydrous dichloromethane.

7. The method for preparing the pyridine-containing Zanthoxylum bungeanum ether derivative according to claim 5, characterized in that: In step (2), the base in the alkaline conditions is K2CO3, the reaction molar ratio of intermediate a to the base is 1:1-1:1.5, the molar ratio of intermediate a to dibromoalkane is 1:1.5-1:3, the reaction temperature is 70-90°C, and the reaction solvent is anhydrous acetonitrile.

8. The method for preparing the pyridine-containing Zanthoxylum bungeanum ether derivative according to claim 5, characterized in that: In step (3), the base in the alkaline conditions is K2CO3, the reaction molar ratio of intermediate b to the base is 1:1-1:1.5, the molar ratio of intermediate a to 4-mercaptopyridine / 2-mercaptopyridine is 1:1-1:1.5, the reaction temperature is 80°C, and the reaction solvent is anhydrous acetonitrile.

9. The method for preparing the pyridine-containing Zanthoxylum bungeanum toxin ether derivative according to claim 5, characterized in that: In step (4), the preparation method of the intermediate d comprises the following steps: different amines reacting with compound II under the catalysis of triethylamine to produce intermediate d, wherein the molar ratio of amine to compound II and triethylamine is 1:1.5:1.5, the reaction temperature is 0°C, and the reaction solvent is anhydrous dichloromethane; Wherein, R1 and R2 are the same as those described in any one of claims 1 to 4, and R3 is selected from Br, Cl or I; In step (4), the molar ratio of intermediate c to intermediate d is 1:2-1:4, the reaction temperature is 70-90° C., and the reaction solvent is anhydrous acetonitrile.

10. Use of the pyridine-containing Zanthoxylum bungeanum ether derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of antibacterial drugs.

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